Mutations in the C9orf72 gene are one of the most common causes of both familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) – two related neurodegenerative conditions that can occur on their own or, at times, concurrently. Wave Life Sciences – a clinical stage genetic medicines company – is hoping to potentially treat both C9-ALS and C9-FTD with WVE-004, an investigational treatment currently in a Phase 1b/2a clinical trial.

WVE-004 is an antisense oligonucleotide (ASO). ASOs are small, single strands of DNA and/or RNA that are easily absorbed by cells, where they attach themselves to “messenger” mRNA strands. They can then, in effect, “turn down” a gene, disrupting the cell’s natural production of a particular protein. This is useful in treating genetic conditions, where mutations in our DNA can cause cells to produce harmful proteins or prevent them from producing those that our body needs to function.

The protein produced by the C9orf72 gene is essential to the proper function of both central nervous system and the immune system. However, in some people the gene contains a “hexanucleotide repeat expansion,” which leads to variant mRNA strands which can cause the loss of normal C9orf72 protein function, as well as the production of harmful proteins. This mutation is the most common genetic factor associated with cases of both familial ALS and FTD. WVE-004 specifically targets precursor mRNA strands (“pre-mRNA”) containing the hexanucleotide repeat expansion. According to Wave Life Sciences’ preclinical studies, WVE-004 has the potential to prevent the production of the toxic proteins while preserving normal C9orf72 function in animal models of ALS.

In order to efficiently test the drug’s potential in both FTD and ALS, Wave has elected to use a “basket-like” model for its FOCUS-C9 Phase 1b/2a trial, enrolling participants with both conditions in one trial. Basket trials are common in studies of different cancers that can be caused by the same genetic mutation or share similar biomarkers. They allow one treatment to be more efficiently tested in multiple related conditions, rather than pursuing an individual trial for each disease.

The trial also follows an “adaptive” design. This means that trial data will be reviewed by an independent committee of scientists, who will be able to recommend changes to the team at Wave regarding the amount and frequency of dosing throughout the course of the trial.

“The way WVE-004 is predicted to behave in the body based upon animal studies allowed us to design FOCUS-C9 to be adaptive, enabling data-driven decisions regarding dose level and frequency as the trial proceeds and potentially accelerating time understanding whether WVE-004 has the potential to be a future treatment,” said Michael Panzara, M.D., MPH, Chief Medical Officer and Head of Therapeutics Discovery and Development at Wave Life Sciences. “Opening the FOCUS-C9 trial to those diagnosed with C9orf72-associated ALS or FTD may also help us pursue both indications in the future.” Wave anticipates generating clinical data through 2022 that will enable decision-making on next steps for the WVE-004 program.

Dosing in the FOCUS-C9 trial was announced in July of 2021, and the study is still currently recruiting as of October 2021, with sites currently open in Australia, Canada, Ireland, and the Netherlands.

For more information about the FOCUS-C9 study, visit ALS TDI’s Clinical Trials database. To learn more about ALS TDI’s research to end ALS, click here.